Spatial Aspects of Oncogenic Signaling Determine Response to Combination Therapy in Slice Explants from Kras ‐driven Lung Tumors

ABSTRACT A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision‐cut slices from Kras‐driven non‐small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC). In addition, high inter‐ and intra‐tumor variability is detected, particularly of MAPK and mTORC1 activity. Using short‐term treatment of slice explants, we show that cytotoxic responses to combination MAPK and PI3K/mTOR inhibition correlate with the spatially‐defined activities of both pathways. Thus, while genetic drivers determine histopathology spectra, histopathology‐associated and spatially‐variable signaling activities determine drug sensitivity. Our study endorses that spatial aspects of signaling heterogeneity are considered in clinical diagnostic settings, particularly to guide the selection of drug combinations.
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research